We have previously established that rat and human hepatic HMG- CoA reductase activity is modulated in vitro and in vivo in a bicyclic cascade system involving reversible phosphorylation of both HMG-CoA reductase and reductase kinase. We have also demonstrated that enzymic activity of HMG-CoA reductase is also modulated in vitro by a protein kinase C-mediated phosphorylation. Recently, we have purified and characterized a low molecular weight (110,000 Da) Ca2+, calmodulin-dependent protein kinase from rat brain cytosol. This kinase phosphorylates histone H1, synapsin 1, and purified HMG-CoA reductase as major substrates. The molecular weight of the holoenzyme, substrate specificity, subunit protein composition, subunit autophosphorylation, subunit isoelectric points, and subunit phosphopeptide analysis suggest that kinase of Mr 110,000 may be different from other previously reported Ca2, calmodulin dependent kinase of purified HMG-CoA reductase revealed a stoichiometry of approximately one mole of phosphate/mole of 100,000 Da enzyme. Dephosphorylation of phosphorylated and inactivated native and purified HMG-CoA reductase revealed a time-dependent loss of 32P-bound radioactivity and reactivation of enzyme activity. Recently in HepG-2 cells we have also investigated the short- term (reversible phosphorylation) and long-term (decreased protein synthesis) control of HMG-CoA reductase by utilizing ligands such as LDL and 25-hydroxycholesterol. During the past year we have utilized the low molecular weight Ca2+, calmodulin-dependent kinase to evaluate the post- translational modification of apolipoprotein A-I by reversible phosphorylation. The reversible covalent phosphorylation of apoA-I may play a pivitol role in apoA-I synthesis and/or metabolism.